DESCRIPTION: Background and Study Objective: Posttraumatic headaches (PTHAs) following mild traumatic brain injury (mTBI) are common, often refractory to standard therapies, and can progress to become a debilitating chronic pain syndrome. Studies of the centrally acting alpha-1 adrenergic receptor (AR) blocker prazosin for treating combat-related posttraumatic stress disorder (PTSD) have coincidentally shown evidence for ameliorating co- morbid headaches (HAs). A large open-label case series and anecdotal reports have additionally noted beneficial effect of prazosin on HAs, in particular, those following blast mTBI. The objective of the proposed study is to rigorously evaluate the efficacy of prazosin for prophylaxis of chronic PTHA following combat mTBI. Study Design and Methods: This is a double-blind placebo-controlled clinical trial based on International Headache Society Guidelines for migraine prophylactic drug studies. The trial length is 16 weeks, including a 4-week pre-treatment screening period followed by a 12-week treatment period, in which participants will be randomized 1:1 to prazosin or placebo. Primary outcome measures will include change from baseline in HA frequency and cumulative HA hours. Secondary outcome measures will include change in other HA measures, PTSD symptoms, sleep quality, depression, alcohol use, cognition, health-related quality of life, and global clinical status. Based on a power analysis for the primary outcome measures, we will need 37 subjects per group to achieve 80% power using a 5% Type I error level. Career Goals: My primary career goal is to combine research and service, working with a population whose needs are diverse and challenging. The VA Healthcare System provides an excellent opportunity for this. Neurologic issues are of particular relevance to Veterans, both as service-related and across the life-span. My intentions in the proposed study are to evaluate a potential treatment for a condition that significantly impacts the welfare of Veterans, as well as to lay the foundation for future studies of the pathophysiology of PTHAs. The demonstration of favorable effects of prazosin on PTSD, sleep disruption, and likely on PTHAs suggests a common pathway involving the alpha-1 adrenergic system. Characterization of this pathway would be expected to foster development of more precisely targeted treatments. For example, HAs are a leading cause for opioid prescribing, with opiate use becoming a public health issue for both the Department of Defense and the VA. Identifying noradrenergic mechanisms in PTHAs could serve as a foundation for efforts to reduce the use of opiates for treating this condition. The Northwest Network Mental Illness Research, Education, and Clinical Center has taken a multi-faceted approach to addressing some of these questions, with several related ongoing studies, including development of a PET tracer for alpha ARs. A long-term goal is to integrate my background in nuclear medicine/PET imaging with the expertise I hope to develop in TBI and HA neurology. Key Elements of the Research Career Development Plan: (1) Develop competence in designing and conducting human clinical trials; (2) Obtain a strong conceptual base for current and future research efforts through didactic and other training; (3) Gain experience in analyzing/interpreting results and publishing/presenting findings; (4) Learn grantsmanship skills; (5) Develop solid clinical expertise in the subspecialties of mTBI and HA evaluation and management; (6) Obtain Board Certification in neurology. Mentoring/Training Plan: My team of mentors can provide the depth of clinical training I need to become a HA expert and nurture my growth as a competent, independent clinical researcher though one-on-one apprenticeship training. Other elements of my training plan include: (1) A didactic training program with selected courses relevant to my current and long-term research interests; (2) Participation in seminars and educational programs relevant to TBI and HAs design and conduct of human clinical trials, and grant writing; (3) Experience in oral and written presentation of research findings.